This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: 118/13/1347    most recent CIRCULATIONAHA.108.784289v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Schulz, E. Articles by Keaney, J. F. Search for Related Content PubMed PubMed Citation Articles by Schulz, E. Articles by Keaney, J. F., Jr Related Collections Energy metabolism Endothelium/vascular type/nitric oxide Other Vascular biology Related Article

(Circulation. 2008;118:1347-1357.)
© 2008 American Heart Association, Inc.

Molecular Cardiology

Suppression of the JNK Pathway by Induction of a Metabolic Stress Response Prevents Vascular Injury and Dysfunction

Eberhard Schulz, MD^*; Jörn Dopheide, MD^*; Swenja Schuhmacher, BS; Shane R. Thomas, PhD; Kai Chen, MD, PhD; Andreas Daiber, PhD; Philip Wenzel, MD; Thomas Münzel, MD; John F. Keaney, Jr, MD

From the Department of Cardiology, 2nd Medical Clinic of the University Hospital Mainz, Johannes Gutenberg University, Mainz, Germany (E.S., J.D., S.S., A.D., P.W., T.M.), and Division of Cardiovascular Medicine, Department of Medicine, University of Massachusetts Medical School, Worcester, Mass (S.R.T., K.C., J.F.K.).

Correspondence to Eberhard Schulz, MD, Department of Cardiology, Johannes Gutenberg University, 55101 Mainz, Germany. E-mail dreberhard. schulz{at}nexgo.de

Received April 8, 2008; accepted July 10, 2008.

Background— Oxidative injury and dysfunction of the vascular endothelium are early and causal features of many vascular diseases. Single antioxidant strategies to prevent vascular injury have met with mixed results.

Methods and Results— Here, we report that induction of a metabolic stress response with adenosine monophosphate kinase (AMPK) prevents oxidative endothelial cell injury. This response is characterized by stabilization of the mitochondrion and increased mitochondrial biogenesis, resulting in attenuation of oxidative c-Jun N-terminal kinase (JNK) activation. We report that peroxisome proliferator coactivator 1 is a key downstream target of AMPK that is both necessary and sufficient for the metabolic stress response and JNK attenuation. Moreover, induction of the metabolic stress response in vivo attenuates reactive oxygen species–mediated JNK activation and endothelial dysfunction in response to angiotensin II in wild-type mice but not in animals lacking either the endothelial isoform of AMPK or peroxisome proliferator coactivator 1.

Conclusion— These data highlight AMPK and peroxisome proliferator coactivator 1 as potential therapeutic targets for the amelioration of endothelial dysfunction and, as a consequence, vascular disease.

---

 

CLINICAL PERSPECTIVE

Related Article:

Clinical Summaries
Circulation 2008 118: 1307-1308. [Extract] [Full Text]

This article has been cited by other articles:

				Z. Ungvari, N. Labinskyy, P. Mukhopadhyay, J. T. Pinto, Z. Bagi, P. Ballabh, C. Zhang, P. Pacher, and A. Csiszar Resveratrol attenuates mitochondrial oxidative stress in coronary arterial endothelial cells Am J Physiol Heart Circ Physiol, November 1, 2009; 297(5): H1876 - H1881. [Abstract] [Full Text] [PDF]

				J. Xu and M.-H. Zou Molecular Insights and Therapeutic Targets for Diabetic Endothelial Dysfunction Circulation, September 29, 2009; 120(13): 1266 - 1286. [Full Text] [PDF]

				B. Fisslthaler and I. Fleming Activation and Signaling by the AMP-Activated Protein Kinase in Endothelial Cells Circ. Res., July 17, 2009; 105(2): 114 - 127. [Abstract] [Full Text] [PDF]

				S. J. Peterson, D. H. Kim, M. Li, V. Positano, L. Vanella, L. F. Rodella, F. Piccolomini, N. Puri, A. Gastaldelli, C. Kusmic, et al. The L-4F mimetic peptide prevents insulin resistance through increased levels of HO-1, pAMPK, and pAKT in obese mice J. Lipid Res., July 1, 2009; 50(7): 1293 - 1304. [Abstract] [Full Text] [PDF]

				A. Csiszar, N. Labinskyy, J. T. Pinto, P. Ballabh, H. Zhang, G. Losonczy, K. Pearson, R. de Cabo, P. Pacher, C. Zhang, et al. Resveratrol induces mitochondrial biogenesis in endothelial cells Am J Physiol Heart Circ Physiol, July 1, 2009; 297(1): H13 - H20. [Abstract] [Full Text] [PDF]